CN115944609A - Isoniazid inhalation solution and preparation method and application thereof - Google Patents
Isoniazid inhalation solution and preparation method and application thereof Download PDFInfo
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- CN115944609A CN115944609A CN202211166151.5A CN202211166151A CN115944609A CN 115944609 A CN115944609 A CN 115944609A CN 202211166151 A CN202211166151 A CN 202211166151A CN 115944609 A CN115944609 A CN 115944609A
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- isoniazid
- inhalation solution
- water
- regulator
- inhalation
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- QRXWMOHMRWLFEY-UHFFFAOYSA-N isoniazide Chemical compound NNC(=O)C1=CC=NC=C1 QRXWMOHMRWLFEY-UHFFFAOYSA-N 0.000 title claims abstract description 69
- 229960003350 isoniazid Drugs 0.000 title claims abstract description 68
- 229940041682 inhalant solution Drugs 0.000 title claims abstract description 40
- 238000002360 preparation method Methods 0.000 title claims abstract description 29
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 30
- 239000003814 drug Substances 0.000 claims abstract description 28
- 230000003204 osmotic effect Effects 0.000 claims abstract description 14
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 20
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 20
- 239000007788 liquid Substances 0.000 claims description 19
- 238000003756 stirring Methods 0.000 claims description 19
- 239000000243 solution Substances 0.000 claims description 17
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 15
- 238000001914 filtration Methods 0.000 claims description 14
- 201000008827 tuberculosis Diseases 0.000 claims description 13
- 238000001514 detection method Methods 0.000 claims description 12
- 239000004698 Polyethylene Substances 0.000 claims description 11
- 238000011049 filling Methods 0.000 claims description 11
- 238000004806 packaging method and process Methods 0.000 claims description 11
- 229920000573 polyethylene Polymers 0.000 claims description 11
- 238000000034 method Methods 0.000 claims description 10
- 239000011780 sodium chloride Substances 0.000 claims description 10
- 239000002994 raw material Substances 0.000 claims description 9
- 238000007789 sealing Methods 0.000 claims description 9
- 239000008215 water for injection Substances 0.000 claims description 8
- 239000007864 aqueous solution Substances 0.000 claims description 7
- ZGTMUACCHSMWAC-UHFFFAOYSA-L EDTA disodium salt (anhydrous) Chemical compound [Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O ZGTMUACCHSMWAC-UHFFFAOYSA-L 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- -1 polyethylene Polymers 0.000 claims description 6
- 229910052782 aluminium Inorganic materials 0.000 claims description 5
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 claims description 5
- 239000003708 ampul Substances 0.000 claims description 5
- 239000002131 composite material Substances 0.000 claims description 5
- 238000007689 inspection Methods 0.000 claims description 5
- 239000004033 plastic Substances 0.000 claims description 5
- 229920003023 plastic Polymers 0.000 claims description 5
- 229920000728 polyester Polymers 0.000 claims description 5
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 claims description 4
- 239000010419 fine particle Substances 0.000 claims description 4
- 208000015181 infectious disease Diseases 0.000 claims description 4
- 102100032341 PCNA-interacting partner Human genes 0.000 claims description 3
- 101710196737 PCNA-interacting partner Proteins 0.000 claims description 3
- 238000007906 compression Methods 0.000 claims description 3
- 230000006835 compression Effects 0.000 claims description 3
- 238000002663 nebulization Methods 0.000 claims description 3
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 2
- 229930195725 Mannitol Natural products 0.000 claims description 2
- 238000007664 blowing Methods 0.000 claims description 2
- 239000003651 drinking water Substances 0.000 claims description 2
- 235000020188 drinking water Nutrition 0.000 claims description 2
- 239000000594 mannitol Substances 0.000 claims description 2
- 235000010355 mannitol Nutrition 0.000 claims description 2
- 229910000403 monosodium phosphate Inorganic materials 0.000 claims description 2
- 235000019799 monosodium phosphate Nutrition 0.000 claims description 2
- 239000006199 nebulizer Substances 0.000 claims description 2
- 239000001103 potassium chloride Substances 0.000 claims description 2
- 235000011164 potassium chloride Nutrition 0.000 claims description 2
- 239000008213 purified water Substances 0.000 claims description 2
- 235000002639 sodium chloride Nutrition 0.000 claims description 2
- 239000001509 sodium citrate Substances 0.000 claims description 2
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 claims description 2
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 claims description 2
- 239000003607 modifier Substances 0.000 claims 1
- 239000008181 tonicity modifier Substances 0.000 claims 1
- 229940079593 drug Drugs 0.000 abstract description 10
- 210000004185 liver Anatomy 0.000 abstract description 8
- 210000003734 kidney Anatomy 0.000 abstract description 6
- 210000004072 lung Anatomy 0.000 abstract description 5
- 230000017531 blood circulation Effects 0.000 abstract description 3
- 230000004060 metabolic process Effects 0.000 abstract description 3
- 230000000241 respiratory effect Effects 0.000 abstract description 3
- 239000003795 chemical substances by application Substances 0.000 abstract 2
- 239000000203 mixture Substances 0.000 description 13
- 239000000126 substance Substances 0.000 description 8
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- 238000000889 atomisation Methods 0.000 description 4
- 238000009472 formulation Methods 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 239000000443 aerosol Substances 0.000 description 3
- 239000012535 impurity Substances 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 208000008128 pulmonary tuberculosis Diseases 0.000 description 3
- 238000012859 sterile filling Methods 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 241000193830 Bacillus <bacterium> Species 0.000 description 2
- 208000009079 Bronchial Spasm Diseases 0.000 description 2
- 208000014181 Bronchial disease Diseases 0.000 description 2
- 206010006482 Bronchospasm Diseases 0.000 description 2
- 208000035473 Communicable disease Diseases 0.000 description 2
- 206010011224 Cough Diseases 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 230000015556 catabolic process Effects 0.000 description 2
- 238000006731 degradation reaction Methods 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- AEUTYOVWOVBAKS-UWVGGRQHSA-N ethambutol Chemical compound CC[C@@H](CO)NCCN[C@@H](CC)CO AEUTYOVWOVBAKS-UWVGGRQHSA-N 0.000 description 2
- 238000010579 first pass effect Methods 0.000 description 2
- 238000011010 flushing procedure Methods 0.000 description 2
- 210000001035 gastrointestinal tract Anatomy 0.000 description 2
- 229910021645 metal ion Inorganic materials 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 239000013618 particulate matter Substances 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 101100468575 Arabidopsis thaliana RH25 gene Proteins 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- 230000001133 acceleration Effects 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000008021 deposition Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 229940072185 drug for treatment of tuberculosis Drugs 0.000 description 1
- 229940124274 edetate disodium Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 229960000285 ethambutol Drugs 0.000 description 1
- XZBIXDPGRMLSTC-UHFFFAOYSA-N formohydrazide Chemical compound NNC=O XZBIXDPGRMLSTC-UHFFFAOYSA-N 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- OAKJQQAXSVQMHS-UHFFFAOYSA-N hydrazine group Chemical group NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 229960005206 pyrazinamide Drugs 0.000 description 1
- IPEHBUMCGVEMRF-UHFFFAOYSA-N pyrazinecarboxamide Chemical compound NC(=O)C1=CN=CC=N1 IPEHBUMCGVEMRF-UHFFFAOYSA-N 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- JQXXHWHPUNPDRT-WLSIYKJHSA-N rifampicin Chemical compound O([C@](C1=O)(C)O/C=C/[C@@H]([C@H]([C@@H](OC(C)=O)[C@H](C)[C@H](O)[C@H](C)[C@@H](O)[C@@H](C)\C=C\C=C(C)/C(=O)NC=2C(O)=C3C([O-])=C4C)C)OC)C4=C1C3=C(O)C=2\C=N\N1CC[NH+](C)CC1 JQXXHWHPUNPDRT-WLSIYKJHSA-N 0.000 description 1
- 229960001225 rifampicin Drugs 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to an isoniazid inhalation solution agent, a preparation method and application thereof, wherein the inhalation solution agent comprises isoniazid, an osmotic pressure regulator, a PH regulator and water; wherein the PH regulator and the isoniazid are 3-5% by volume/weight ratio, and the water and the isoniazid are 10-20% by volume/weight ratio. The invention has the advantages that the inhalation preparation is directly acted on the lung through the mouth and the nose, can be gathered into higher concentration in the lung and enters a respiratory and blood circulation system, thereby achieving the purpose of whole body medication, greatly reducing the metabolic process of the medicament by liver and kidney and greatly reducing the liver and kidney damage of a patient.
Description
Technical Field
The invention relates to the technical field of isoniazid preparation, in particular to an isoniazid inhalation solution and a preparation method and application thereof.
Background
Isoniazid (Isoniazid) chemical name: 4-pyridine carbohydrazide, together with rifampicin, ethambutol and pyrazinamide, are first-line antituberculosis drugs. Isoniazid was invented in 1952 as a chemical drug, which radically changes the treatment of tuberculosis, and most doctors still consider it to be an indispensable main drug for the treatment of tuberculosis in the history of about 70 years although some tubercle bacillus infected by patients has developed drug resistance.
Tuberculosis is a chronic infectious disease caused by infection of tubercle bacillus, which can invade various organs of human body, and is common as pulmonary tuberculosis, and is one of serious infectious diseases seriously harming the health of people. At present, china is still one of 30 tuberculosis high-load countries all over the world, about 90 thousands of new tuberculosis patients are treated every year, and the new tuberculosis patients are located at the 3 rd position all over the world. At present, the number of tuberculosis patients in China is still more, the prevention and treatment situation of tuberculosis in the areas of the middle and the west and in rural areas is severe, meanwhile, the successful treatment rate of tuberculosis patients reaches over 90 percent in 2025 years by the nation, and in order to achieve the aim, the prevention and treatment of tuberculosis are not slow.
Among the tuberculosis treatment drugs, the isonicotinus injection is marketed in Japan in 1960, and has the characteristics of obvious curative effect on tuberculosis treatment and few adverse reactions for more than 50 years. Isoniazid, chemical name: 4-pyridine formhydrazide, which has the following structural formula:
at present, various researches are carried out on isoniazid preparations, such as the development of new formulations, such as a frozen Dingzhi preparation or an optimized prescription, mainly embodied by carrying out optimization adjustment on the basis of the prescription of a reference preparation, such as the addition of a metal chelating agent edetate disodium, an antioxidant sodium bisulfite and the like, and directly changing the composition types of the prescription. However, most of the new preparations have complicated preparation processes, high difficulty in mass production and inconvenient clinical use.
Disclosure of Invention
The invention aims to overcome the defects in the prior art, and provides an isoniazid inhalation solution, a preparation method and application thereof.
The invention is realized by the following technical scheme: providing an isoniazid inhalation solution, wherein the raw materials of the inhalation solution comprise isoniazid, an osmotic pressure regulator, a pH regulator and water; wherein the PH regulator and the isoniazid are 3-5% by volume/weight ratio, and the water and the isoniazid are 10-20% by volume/weight ratio.
By the technical scheme, the isoniazid inhalation solution can replace oral administration and other dosage forms, is directly inhaled from the mouth and the nose, avoids the first pass effect of the liver and the damage and degradation of gastrointestinal tracts, can be gathered into higher concentration in the lung, and then enters a respiratory and blood circulation system, so that the purpose of whole body treatment is achieved, the metabolic process of the liver and the kidney to the medicine is greatly reduced, and the liver and kidney damage to a patient is greatly reduced; further fills the blank of the current domestic and foreign markets, provides a novel, safe and effective drug delivery mode for isoniazid, and provides a brand new solution for the treatment of pulmonary tuberculosis.
Furthermore, the single dose of the raw materials of the inhalation solution comprises 100-200 mg of isoniazid, 10-30 mg of osmotic pressure regulator, 30-50 mg of pH regulator and 1000-2000 mg of water in parts by weight.
Through the technical scheme, the composition is simple, the pH value control range meets the safety requirement of clinical medication, and meanwhile, the osmotic pressure is close to isotonic, so that bronchospasm and cough caused by inhalation of isoniazid solution can be reduced; the prepared preparation has stable quality and high atomization efficiency, and the quality is not lower than that of the original grinding injection on the market; adopts a milder pH regulator to regulate the pH, relatively reduces the attack of hydrochloric acid as a pH regulator proton on a hydrazine group, can greatly slow down the hydrolysis of isoniazid, and reduces the generation of toxic impurities.
Furthermore, the osmolality of the inhalation solution is 270-310 mOsm/L, and the clinical medication requirement can be met
Further, the osmotic pressure regulator is one or more of sodium chloride, potassium chloride and mannitol.
Further, the pH regulator is one or more of sodium hydroxide, hydrochloric acid, sodium dihydrogen phosphate, citric acid and sodium citrate.
Further, the water is selected from drinking water, purified water or water for injection.
The invention provides a method for preparing the isoniazid inhalation solution, which comprises the following steps:
s1, preparing a liquid according to the raw material proportion; dissolving an osmotic pressure regulator in water with the total volume of 80-90% and the temperature of 30-60 ℃, and stirring until the osmotic pressure regulator is completely dissolved to form a water solution; adding isoniazid into the aqueous solution, stirring until the isoniazid is completely dissolved, adding a pH regulator to regulate the pH value to 6.3-6.7, and uniformly stirring;
s2, fixing the volume; adding water to the total volume in the step S1, and uniformly stirring to prepare an intermediate liquid medicine;
s3, detecting quality;
s4, filtering and encapsulating; and filtering qualified intermediate liquid medicine by 0.45-micrometer and 0.22-micrometer filters in sequence, adopting blowing, filling and sealing integrated filling and sealing equipment, and filling into 2ml polyethylene plastic ampoule bottles.
S5, leak detection, lamp detection and label sticking are carried out by adopting a high-voltage discharge leak detector;
s6, carrying out secondary sealing packaging by adopting a polyester/aluminum/polyethylene medicinal composite film;
and S7, packaging the finished product into a warehouse, and performing quality full inspection to obtain a qualified solution type isoniazid inhalation solution.
By adopting the technical scheme, the isoniazid inhalation solution provided by the invention is single-dose, adopts polyethylene packaging and sterilization filtration processes, can greatly improve the impurity level of the preparation, is convenient and safe in clinical use process, and better improves the adaptability of patients; moreover, the whole preparation process is simple, the equipment cost is low, and the industrial production is convenient.
Further, in step S1, the pipeline is flushed with 0.02-0.05% EDTA-2Na before liquid preparation.
By the technical scheme, the isoniazid inhalation solution is sensitive to metal ions, so that the pipeline is flushed with 0.02-0.05% of EDTA-2Na before the solution preparation in production, and batch quality difference caused by the metal ions in the production process is prevented.
Further, after the isoniazid inhalation solution is atomized by a PARI PlusTM compression atomizer, the aerodynamic mass median diameter is 2-5 μm, the percentage of fine particles is 30% -70%, and the administration time after atomization is 10-30min.
In addition, the invention provides an application of the isoniazid inhalation solution, namely an application of the isoniazid inhalation solution in preparing a medicine for treating pulmonary tuberculosis infection.
The invention has the beneficial effects that: the isoniazid inhalation solution can replace oral administration and other dosage forms, is directly inhaled by mouth and nose, avoids the first pass effect of liver and the damage and degradation of gastrointestinal tract, can be aggregated into higher concentration in lung, and then enters a respiratory and blood circulation system, thereby achieving the purpose of whole body treatment, greatly reducing the metabolic process of liver and kidney to the medicine, and greatly reducing the liver and kidney damage to patients; in addition, the isoniazid inhalation solution has simple components, the pH value control range meets the safety requirement of clinical medication, and meanwhile, the osmotic pressure is close to isotonic, so that the bronchospasm and cough caused by the isoniazid inhalation solution can be reduced; and the prepared preparation has stable quality and high atomization efficiency.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
The examples, in which specific conditions are not specified, were carried out according to conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products available commercially. In the following examples, isoniazid is used in an anhydrous basis.
Example 1
Prescription:
| prescription composition | Dosage of |
| Isoniazid | 100g |
| Sodium chloride | 20g |
| 0.5mol/l hydrochloric acid solution | Proper amount of |
| Water for injection | Adding to 2L |
The preparation process comprises the following steps:
s1, preparing a liquid according to the raw material ratio; dissolving sodium chloride in water for injection with the total volume of 90% and the temperature of 60 ℃, and stirring until the sodium chloride is completely dissolved to form an aqueous solution; adding isoniazid into the aqueous solution, stirring until the isoniazid is completely dissolved, then adding 0.5mol/l hydrochloric acid solution to adjust the pH value to 6.6, and stirring uniformly;
s2, fixing the volume; adding water to the full volume in the step S1, and uniformly stirring to prepare an intermediate liquid medicine;
s3, detecting quality;
s4, filtering and encapsulating; and (3) performing coarse filtration and fine filtration on the qualified intermediate liquid medicine sequentially by 0.45 mu m and 0.22 mu m, and filling the intermediate liquid medicine into a 2mL polyethylene plastic ampoule bottle by adopting a BFS sterile filling process.
S5, leak detection, lamp detection and label pasting are carried out by adopting a high-voltage discharge leak detector;
s6, carrying out secondary sealing packaging by adopting a polyester/aluminum/polyethylene medicinal composite film;
and S7, packaging the finished product into a warehouse, and performing quality full inspection to obtain a qualified solution type isoniazid inhalation solution.
Example 2
Prescription:
| prescription composition | Amount of the composition |
| Isoniazid | 100g |
| Sodium chloride | 20g |
| 0.5mol/l hydrochloric acid solution | Proper amount of |
| Water for injection | To 2L |
The preparation process comprises the following steps:
s1, flushing a pipeline by using 0.02% of EDTA-2Na, and preparing a liquid according to the mixture ratio of the raw materials; dissolving sodium chloride in water for injection with the total volume of 90% and the temperature of 30 ℃, and stirring until the sodium chloride is completely dissolved to form an aqueous solution; adding isoniazid into the aqueous solution, stirring until the isoniazid is completely dissolved, then adding 0.5mol/l hydrochloric acid solution to adjust the pH value to 6.7, and stirring uniformly;
s2, fixing the volume; adding water to the full volume in the step S1, and uniformly stirring to prepare an intermediate liquid medicine;
s3, detecting quality;
s4, filtering and encapsulating; and (3) sequentially carrying out coarse filtration with the thickness of 0.45 mu m and fine filtration with the thickness of 0.22 mu m on the intermediate liquid medicine qualified in detection, and filling the intermediate liquid medicine into a 2mL polyethylene plastic ampoule bottle by adopting a BFS sterile filling process.
S5, leak detection, lamp detection and label pasting are carried out by adopting a high-voltage discharge leak detector;
s6, carrying out secondary sealing packaging by adopting a polyester/aluminum/polyethylene medicinal composite film;
and S7, packaging the finished product into a warehouse, and performing quality full inspection to obtain a qualified solution type isoniazid inhalation solution.
Example 3
Prescription:
| prescription composition | Amount of the composition |
| Isoniazid | 100g |
| Sodium chloride | 20g |
| 0.5mol/l hydrochloric acid solution | Proper amount of |
| Water for injection | Adding to 2L |
The preparation process comprises the following steps: in the same way as in example 2, the liquid preparation and the filling and nitrogen filling are added, and the residual oxygen content of the secondary package in the finished product is controlled to be below 3 percent.
Example 4 to example 8: preparation of formulations of different pH
Prescription:
| prescription composition | Dosage of |
| Isoniazid | 100g |
| Sodium chloride | 20g |
| 0.5mol/l hydrochloric acid solution | Proper amount of |
| pH 3.0 citric acid buffer | Proper amount of |
| Water for injection | To 2L |
The preparation process comprises the following steps:
s1, flushing a pipeline by using 0.05% of EDTA-2Na, taking injection water with the prescription amount of 90%, sequentially adding the main drug and the osmotic pressure regulator with the prescription amount, stirring and dissolving, evenly dividing into five parts, respectively adjusting the pH value to 6.0, 6.5 and 7.0 by using a hydrochloric acid pH regulator, adjusting the pH value to 6.0 and 7.0 by using a citric acid buffer pH regulator, and uniformly stirring;
s2, fixing the volume; respectively adding water into the step S1 to fix the volume to the full volume, and uniformly stirring to prepare an intermediate liquid medicine;
s3, detecting the quality;
s4, filtering and encapsulating; and (3) sequentially carrying out coarse filtration with the thickness of 0.45 mu m and fine filtration with the thickness of 0.22 mu m on the intermediate liquid medicine qualified in detection, and filling the intermediate liquid medicine into a 2mL polyethylene plastic ampoule bottle by adopting a BFS sterile filling process.
S5, leak detection, lamp detection and label pasting are carried out by adopting a high-voltage discharge leak detector;
s6, carrying out secondary sealing packaging by adopting a polyester/aluminum/polyethylene medicinal composite film;
and S7, packaging the finished product into a warehouse, and performing quality full inspection to obtain a qualified solution type isoniazid inhalation solution.
Test example 1
Taking the samples of the examples 1-3 of the invention, examining the stability under the acceleration conditions of 40 ℃ +/-2 ℃ and RH25% +/-5%, sampling in 0, 3 and 6 months respectively, and examining the properties, osmotic pressure molar concentration, related substances, water loss rate and content of the samples, and the results are shown in Table 1. The content and related substance determination method refers to the content determination and related substance determination method under the entry registration standard item of USP43-NF38 and EP10.0 isoniazid raw material drugs and isoniazid injection, the limit of the content determination is 95.0-105.0%, and the limit of the total impurities of related substances is estimated to be 2.0%.
TABLE 1 comparison of the stability of formulations with respect to the absence or presence of nitrogen charge
And (4) analyzing results: from the comparison results, the product is stable to oxygen, and nitrogen is required to be filled for protection in the production process.
Test example 2
Samples of examples 1, 4 to 8 of the present invention with different pH values were taken, stability was examined under accelerated conditions of 40 ℃. + -. 2 ℃ and RH 25%. + -. 5%, and samples were taken at 0, 3 and 6 months, respectively, to examine properties, pH values, related substances and contents of the samples, and the results are shown in Table 2.
TABLE 2 comparison of stability of formulations at different pH
And (4) analyzing results: comparing the stability research results of different pH preparations, the product is regulated by citric acid buffer solution in the pH regulator type, and the pH range of the preparation is controlled to be 6.0-7.0.
Test example 3
Using a bery PARI BOY compression nebulizer, 2ml of inventive samples, example 1 and example 8, were taken and the parameters of nebulization time, delivery rate and total delivered amount, percent fine particles FPF (%) and aerodynamic mass median diameter MMAD (μm) were recorded and the results are given in table 4.
Note {1}: aerodynamic mass median diameter (MMAD): when the total mass of particles of various sizes smaller than a certain aerodynamic diameter in the particulate matter accounts for 50% of the total particulate matter mass (i.e., the sum of all particles of different sizes), the diameter is referred to as the mass median diameter.
Note {2}: FPF (%): the deposition rate of the drug in the lungs.
And (4) analyzing results: the isoniazid aerosol inhalation solution prepared by the method has good atomization characteristics, the aerosol inhalation administration time can be controlled within 10-20min, the diameter in aerodynamic quality is 2-5 mu m, the percentage of fine particles is 30% -70%, the requirement of aerosol inhalation can be met, and the optimized prescription (embodiment 8) is obviously superior to the original prescription (embodiment 1).
Finally, it should be noted that: although the present invention has been described in detail with reference to the foregoing embodiments, it will be apparent to those skilled in the art that modifications may be made to the embodiments or portions thereof without departing from the spirit and scope of the invention.
Claims (10)
1. An isoniazid inhalation solution, characterized by that, the raw materials of the inhalation solution include isoniazid, osmotic pressure regulator, PH regulator and water; wherein the PH regulator and the isoniazid are 3 to 5 percent in volume/weight ratio; water and isoniazid in a volume/weight ratio of 10-20.
2. The isoniazid inhalation solution of claim 1, wherein the single dose of raw materials of the inhalation solution comprises, by weight, 100-200 mg of isoniazid, 10-30 mg of osmotic pressure regulator, 30-50 mg of ph regulator and 1000-2000 mg of water.
3. The isoniazid inhalation solution of claim 1, wherein the osmolality of the inhalation solution is 270-310 mOsm/L.
4. Isoniazid inhalation solution according to claim 1, characterized in that the tonicity modifier is one or more of sodium chloride, potassium chloride, mannitol.
5. An isoniazid inhalation solution according to claim 1, wherein the PH modifier is one or more of sodium hydroxide, hydrochloric acid, sodium dihydrogen phosphate, citric acid and sodium citrate.
6. Isoniazid inhalation solution according to claim 1, characterized in that the water is selected from drinking water, purified water or water for injection.
7. A process for the preparation of an isoniazid inhalation solution as claimed in any of claims 1 to 6, comprising the steps of:
s1, preparing a liquid according to the raw material ratio; dissolving an osmotic pressure regulator in water with the total volume of 80-90% and the temperature of 30-60 ℃, and stirring until the osmotic pressure regulator is completely dissolved to form an aqueous solution; adding isoniazid into the aqueous solution, stirring until the isoniazid is completely dissolved, adding a pH regulator to regulate the pH value to 6.3-6.7, and uniformly stirring;
s2, fixing the volume; adding water to the total volume in the step S1, and uniformly stirring to prepare an intermediate liquid medicine;
s3, detecting quality;
s4, filtering and encapsulating; and filtering qualified intermediate liquid medicine by 0.45-micrometer and 0.22-micrometer filters in sequence, adopting blowing, filling and sealing integrated filling and sealing equipment, and filling into 2ml polyethylene plastic ampoule bottles.
S5, leak detection, lamp detection and label pasting are carried out by adopting a high-voltage discharge leak detector;
s6, carrying out secondary sealing packaging by adopting a polyester/aluminum/polyethylene medicinal composite film;
and S7, packaging the finished product into a warehouse, and performing quality total inspection to obtain a qualified solution type isoniazid inhalation solution.
8. The method for preparing an isoniazid inhalation solution according to claim 7, wherein in step S1, the tube is flushed with 0.02 to 0.05% of EDTA-2Na before the solution preparation.
9. An isoniazid inhalation solution according to claim 1, wherein the isoniazid inhalation solution has an aerodynamic mass median diameter of 2-5 μm, a percentage of fine particles of 30-70% and a dosing time of 10-30min after nebulization, after nebulization with a PARI plus compression nebulizer.
10. Use of an isoniazid inhalation solution as claimed in any one of claims 1 to 6 for the preparation of a medicament for the treatment of tuberculosis infection.
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| CN1102093A (en) * | 1993-10-23 | 1995-05-03 | 丛繁滋 | Isoniazid aerosol, spray and preparation method thereof |
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| CN111265475A (en) * | 2020-02-28 | 2020-06-12 | 天津金耀药业有限公司 | Isoniazid injection and preparation method thereof |
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| CN1102093A (en) * | 1993-10-23 | 1995-05-03 | 丛繁滋 | Isoniazid aerosol, spray and preparation method thereof |
| CN1134278A (en) * | 1993-11-13 | 1996-10-30 | 丛繁滋 | Aerosol for preventing and curing pulmonary tuberculosis and its preparing method and synergy method |
| US20050084455A1 (en) * | 2003-10-16 | 2005-04-21 | Council Of Scientific & Industrial Research | Inhalable biodegradable microparticles for target-specific drug delivery in tuberculosis and a process thereof |
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